Combination of HDAC inhibitor MS-275 and IL-2 increased anti-tumor effect in a melanoma model via activated cytotoxic T cells

Yukihiko Kato, Ikuyo Yoshino, Chizu Egusa, Tatsuo Maeda, Roberto Pili, Ryoji Tsuboi

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Background: Histone deacetylase (HDAC) inhibitors are immunomodulatory, and demonstrate antitumor activity in various tumor models including malignant melanoma. Objective: The present study examines the effectiveness of IL-2 and HDAC inhibitor MS-275-combination therapy in a murine melanoma model. Methods: B16F10 cells were implanted subcutaneously in C57BL/6 mice which were randomly divided into four groups and treated with either IL-2 by subcutaneous injection, MS-275 by oral gavage (5 days/week, daily for 2 weeks), or a combination of the two agents. Results: MS-275 treatment showed a dose-dependent inhibitory effect on B16 cells in a colonogenic assay. Flow cytometry analysis indicated that MS-275 induced G1 arrest but not apoptosis in vitro, but IL-2 failed to inhibit cell proliferation. The combination of MS-275 and IL-2 had a statistically significant additive inhibitory effect on melanoma tumor weight and volume in vivo. Significantly higher survival was evident in the combination group compared with the control or single-agent groups. The combination therapy produced a greater ratio of CD8+ CD69+ T cells in lymph nodes than was seen in the MS-275-treatment and no-treatment groups among tumoriferous mice. Splenocytes from mice treated with MS-275 and the combination therapy demonstrated greater lysis of melanoma cells in vitro than splenocytes from mice treated with IL-2 or those without treatment. A significant antitumor effect from IL-2 and MS-275-combination therapy in vivo was seen in the increased number of activated CD8+ T cells. Conclusions: These data provide a convincing rationale for considering the role of epigenetics in future treatments for malignant melanoma.

Original languageEnglish (US)
Pages (from-to)140-147
Number of pages8
JournalJournal of Dermatological Science
Volume75
Issue number2
DOIs
StatePublished - 2014
Externally publishedYes

Fingerprint

Histone Deacetylase Inhibitors
T-cells
Interleukin-2
Tumors
Melanoma
T-Lymphocytes
Neoplasms
Therapeutics
Tumor Burden
Flow cytometry
entinostat
Cell proliferation
Subcutaneous Injections
Inbred C57BL Mouse
Epigenomics
Assays
Flow Cytometry
Apoptosis
Lymph Nodes
Cell Proliferation

Keywords

  • Activated CD8-positive T lymphocyte
  • Combination therapy
  • Histone deacetylase inhibitor
  • Interleukin-2
  • Melanoma

ASJC Scopus subject areas

  • Dermatology
  • Biochemistry
  • Molecular Biology
  • Medicine(all)

Cite this

Combination of HDAC inhibitor MS-275 and IL-2 increased anti-tumor effect in a melanoma model via activated cytotoxic T cells. / Kato, Yukihiko; Yoshino, Ikuyo; Egusa, Chizu; Maeda, Tatsuo; Pili, Roberto; Tsuboi, Ryoji.

In: Journal of Dermatological Science, Vol. 75, No. 2, 2014, p. 140-147.

Research output: Contribution to journalArticle

Kato, Yukihiko ; Yoshino, Ikuyo ; Egusa, Chizu ; Maeda, Tatsuo ; Pili, Roberto ; Tsuboi, Ryoji. / Combination of HDAC inhibitor MS-275 and IL-2 increased anti-tumor effect in a melanoma model via activated cytotoxic T cells. In: Journal of Dermatological Science. 2014 ; Vol. 75, No. 2. pp. 140-147.
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AU - Maeda, Tatsuo

AU - Pili, Roberto

AU - Tsuboi, Ryoji

PY - 2014

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N2 - Background: Histone deacetylase (HDAC) inhibitors are immunomodulatory, and demonstrate antitumor activity in various tumor models including malignant melanoma. Objective: The present study examines the effectiveness of IL-2 and HDAC inhibitor MS-275-combination therapy in a murine melanoma model. Methods: B16F10 cells were implanted subcutaneously in C57BL/6 mice which were randomly divided into four groups and treated with either IL-2 by subcutaneous injection, MS-275 by oral gavage (5 days/week, daily for 2 weeks), or a combination of the two agents. Results: MS-275 treatment showed a dose-dependent inhibitory effect on B16 cells in a colonogenic assay. Flow cytometry analysis indicated that MS-275 induced G1 arrest but not apoptosis in vitro, but IL-2 failed to inhibit cell proliferation. The combination of MS-275 and IL-2 had a statistically significant additive inhibitory effect on melanoma tumor weight and volume in vivo. Significantly higher survival was evident in the combination group compared with the control or single-agent groups. The combination therapy produced a greater ratio of CD8+ CD69+ T cells in lymph nodes than was seen in the MS-275-treatment and no-treatment groups among tumoriferous mice. Splenocytes from mice treated with MS-275 and the combination therapy demonstrated greater lysis of melanoma cells in vitro than splenocytes from mice treated with IL-2 or those without treatment. A significant antitumor effect from IL-2 and MS-275-combination therapy in vivo was seen in the increased number of activated CD8+ T cells. Conclusions: These data provide a convincing rationale for considering the role of epigenetics in future treatments for malignant melanoma.

AB - Background: Histone deacetylase (HDAC) inhibitors are immunomodulatory, and demonstrate antitumor activity in various tumor models including malignant melanoma. Objective: The present study examines the effectiveness of IL-2 and HDAC inhibitor MS-275-combination therapy in a murine melanoma model. Methods: B16F10 cells were implanted subcutaneously in C57BL/6 mice which were randomly divided into four groups and treated with either IL-2 by subcutaneous injection, MS-275 by oral gavage (5 days/week, daily for 2 weeks), or a combination of the two agents. Results: MS-275 treatment showed a dose-dependent inhibitory effect on B16 cells in a colonogenic assay. Flow cytometry analysis indicated that MS-275 induced G1 arrest but not apoptosis in vitro, but IL-2 failed to inhibit cell proliferation. The combination of MS-275 and IL-2 had a statistically significant additive inhibitory effect on melanoma tumor weight and volume in vivo. Significantly higher survival was evident in the combination group compared with the control or single-agent groups. The combination therapy produced a greater ratio of CD8+ CD69+ T cells in lymph nodes than was seen in the MS-275-treatment and no-treatment groups among tumoriferous mice. Splenocytes from mice treated with MS-275 and the combination therapy demonstrated greater lysis of melanoma cells in vitro than splenocytes from mice treated with IL-2 or those without treatment. A significant antitumor effect from IL-2 and MS-275-combination therapy in vivo was seen in the increased number of activated CD8+ T cells. Conclusions: These data provide a convincing rationale for considering the role of epigenetics in future treatments for malignant melanoma.

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